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Hematologic Adverse Effects of Standard TB Therapy
Pennan Barry, MD MPHCalifornia Department of Public Health
TB Control Branch
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Hematologic Adverse Effects of Standard TB Therapy
Drug-Resistant TB: A Survival Guide for Clinicians, 2nd ed.
↓WBC ↓PMN ↓Plt ↓RBC Red Cell Aplasia
Hemolytic Anemia
Aplastic Anemia
Rif X X X X X
INH X X X X X X
EMB X X
PZA X X
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Hematologic Adverse Effects of Standard TB Therapy
Drug-Resistant TB: A Survival Guide for Clinicians, 2nd ed.
↓WBC ↓PMN ↓Plt ↓RBC Red Cell Aplasia
Hemolytic Anemia
Aplastic Anemia
Rif X X X X X
INH X X X X X X
EMB X X
PZA X X
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Thrombocytopenia: Rifampin• Risks
– high dose intermittent regimens (up to 6% on biweekly)– cessation and rechallenge
• Immune mediated– Rif antigenic as hapten-albumin complex– Rif dependent Ab fix complement on platelets (GPIb/IX)
• Extremely rapid onset• Can be severe requiring steroids and platelet
transfusion• Complications: subdural hematoma, melena
Holdiness Tubercle 1987 | Mori J Infect Chemotherapy 2010 | Kang Neurological Sciences 2010 | Mehta Tubercle and Lung Dis 1996 | Pereira Br J Haematol 2000
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Thrombocytopenia: Ethambutol
• 2 case reports• Rapid onset after treatment initiation (4-6
days)• Rapid resolution after discontinuation
Holdiness Tubercle 1987 | Prasad Tubercle 1989 | Rabinowitz Chest 1982
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Thrombocytopenia: PZA
• Case reports• Associated with sideroblastic anemia• 1-2 months into treatment
Holdiness Tubercle 1987 | Jain Tubercle 1988 | Roseau Rev Mal Respir 2008
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Thrombocytopenia: INH
• No case reports in last 50 years • package insert :
http://www.versapharm.com/media/productinserts/
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INH: Anemia• Sideroblastic anemia responsive to B6 (also caused by PZA)
– 4-16 weeks into treatment– Microcytic; Normal iron studies– Marrow: normoblastic hyperplasia and ringed
sideroblasts – result of INH effects on pyridoxine metabolism
• Pure red cell aplasia– Quick recovery with INH cessation– Can occur up to 6 mos into Rx– Induced autoimmunity to RBC precursors
• Hemolytic anemia: Coombs’ negative and positive
Holdiness Tubercle 1987 | Loulergue Emerg Infect Dis 2007 | Robinson JAMA 1969 | Liu JAMA 1987
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Bone marrow aspirate shows ringed sideroblasts, Prussian Blue stain; 1000x -- Liu JAMA 1987
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Bone marrow aspirate shows ringed sideroblasts, Prussian Blue stain; 1000x -- Liu JAMA 1987
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Rifampin: Hemolytic anemia
• Associated with rifampin “flu” syndrome• Acute renal failure• RBC-specific antibodies (recognize Lu and I
Ag)• Patterns:
– Escalating antibodies with successive intermittent doses
– Rapid reaction following reintroduction– Random reaction with continuous daily dosing
Holdiness Tubercle 1987 | Neunert Pediatr Blood Cancer 2008 | Pereira Ann Hematol 1991
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INH and Rif: Leukopenia
• Case control study of 1,525 TB patients at a Tokyo hospital 1987-2000
• 36 had WBC fall to <3.0 on TB Rx (1.2% of men; 5.9% of women); 2 had agranulocytosis
• 30 had meds continued: – 19 recovered on Rx; 11 remained leukopenic on Rx
• No difference by regimen (HRE, HRS, HREZ)• Leukopenic pts had lower baseline WBC than
controls (7.2 vs 5.5, p<.001)
Nagayama Kekkaku 2004
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Agranulocytosis
• At least 14 cases reported• Incidence 0.06% at one Japanese hospital• Rif and INH (PZA: 2 case reports) • Can occur simultaneously with
hepatotoxicity• 1-3 months into Rx
Shishido Kekkaku 2003 | www.adverse-effects.com+case_reports.html_ | Jenkins Br Med J 1980 | Wong Chest 1994